Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways.
Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways.
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DOI：
10.1101/gad.261677.115
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发表时间：
2015-08-15
影响因子：
10.5
通讯作者：
Gutmann DH
中科院分区：
文献类型：
--
作者：
Chen YH;Gianino SM;Gutmann DH
In this study, Chen et al. used Nf1 genetically engineered mice coupled with genetic and pharmacologic inhibitor strategies to investigate the mechanisms of neurofibromin control of NSC proliferation and multilineage differentiation. They demonstrate that neurofibromin differentially controls NSC proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways, providing new insights into the roles for the RAS effector pathways in regulating brain NSC function. Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by impaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, we report that neurofibromin differentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways. While PI3K/AKT governs neurofibromin-regulated NSC proliferation, multilineage differentiation is MEK-dependent. Moreover, whereas MEK-regulated multilineage differentiation requires Smad3-induced Jagged-1 expression and Notch activation, MEK/Smad3-regulated Hes1 induction is only responsible for astrocyte and neuronal differentiation. Collectively, these findings establish distinct roles for the RAS effector pathways in regulating brain NSC function.
